Differential Inhibition of Human Nav1.2 Resurgent and Persistent Sodium Currents by Cannabidiol and GS967.

Emily R Mason,Theodore R Cummins

doi:10.3390/ijms21072454

Abstract

Many epilepsy patients are refractory to conventional antiepileptic drugs. Resurgent and persistent currents can be enhanced by epilepsy mutations in the Nav1.2 channel, but conventional antiepileptic drugs inhibit normal transient currents through these channels, along with aberrant resurgent and persistent currents that are enhanced by Nav1.2 epilepsy mutations. Pharmacotherapies that specifically target aberrant resurgent and/or persistent currents would likely have fewer unwanted side effects and be effective in many patients with refractory epilepsy. This study investigated the effects of cannbidiol (CBD) and GS967 (each at 1 μM) on transient, resurgent, and persistent currents in human embryonic kidney (HEK) cells stably expressing wild-type hNav1.2 channels. We found that CBD preferentially inhibits resurgent currents over transient currents in this paradigm; and that GS967 preferentially inhibits persistent currents over transient currents. Therefore, CBD and GS967 may represent a new class of more targeted and effective antiepileptic drugs.

Highlights

While most epilepsy cases respond well to common antiepileptic drugs, about 38% of epilepsy patients experience persistent seizures under conventional epilepsy treatments [1,2,3,4,5,6]
Since we have shown that the enhancement of resurgent current by the SCN8A/Nav1.6 epilepsy mutation N1768D can be selectively inhibited by CBD [45], we tested the ability of these compounds to selectively inhibit INaR in the Nav1.2 channel isoform
Since CBD has been shown to inhibit the enhancement of INaR caused by the Nav1.6 epilepsy mutation N1768D without disturbing the INaT density [45], we predicted that CBD would selectively inhibit INaR and/or INaP over INaT in human embryonic kidney (HEK) cells stably expressing WT Nav1.2

Summary

Introduction

While most epilepsy cases respond well to common antiepileptic drugs, about 38% of epilepsy patients experience persistent seizures under conventional epilepsy treatments [1,2,3,4,5,6] Many of these refractory epilepsies are believed to be manifestations of mutations in SCN2A, the gene for the human voltage-gated sodium channel hNav1.2 [7]. This channel isoform is predominantly expressed in glutamatergic neurons in the brain; and epilepsy mutations in this protein are generally believed to cause a net augmentation of the channel function, leading to hyperexcitability and inappropriate action potential firing. The enhancement of Nav1.2-mediated persistent and resurgent currents by some SCN2A epilepsy mutations is predicted to play a role in epileptogenesis

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Conclusion